Journal of the American College of Cardiology Vol. 62, No. 6, 2013� 2013 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.04.070

STATE-OF-THE-ART PAPER

Abdominal Contributions toCardiorenal Dysfunction in Congestive Heart Failure

Frederik H. Verbrugge, MD,*y Matthias Dupont, MD,* Paul Steels, MD,z Lars Grieten, PHD,*zManu Malbrain, MD, PHD,x W. H. Wilson Tang, MD,k Wilfried Mullens, MD, PHD*zGenk, Diepenbeek, and Antwerp, Belgium; and Cleveland, Ohio

C

From the *Depart

yDoctoral School

Belgium; zBiomed

Hasselt University,

Ziekenhuis Netwe

kDepartment of C

Clinic, Cleveland,

Limburg Clinical R

Foundation Limb

Limburg and Jessa

tionships relevant

Manuscript rece

accepted April 17,

urrent pathophysiological models of congestive heart failure unsatisfactorily explain the detrimental link betweencongestion and cardiorenal function. Abdominal congestion (i.e., splanchnic venous and interstitial congestion)manifests in a substantial number of patients with advanced congestive heart failure, yet is poorly defined.Compromised capacitance function of the splanchnic vasculature and deficient abdominal lymph flow resulting ininterstitial edema might both be implied in the occurrence of increased cardiac filling pressures and renaldysfunction. Indeed, increased intra-abdominal pressure, as an extreme marker of abdominal congestion, iscorrelated with renal dysfunction in advanced congestive heart failure. Intriguing findings provide preliminaryevidence that alterations in the liver and spleen contribute to systemic congestion in heart failure. Finally, gut-derived hormones might influence sodium homeostasis, whereas entrance of bowel toxins into the circulatorysystem, as a result of impaired intestinal barrier function secondary to congestion, might further depress cardiac aswell as renal function. Those toxins are mainly produced by micro-organisms in the gut lumen, with presumablyimportant alterations in advanced heart failure, especially when renal function is depressed. Therefore, in this state-of-the-art review, we explore the crosstalk between the abdomen, heart, and kidneys in congestive heart failure. Thismight offer new diagnostic opportunities as well as treatment strategies to achieve decongestion in heart failure,especially when abdominal congestion is present. Among those currently under investigation are paracentesis,ultrafiltration, peritoneal dialysis, oral sodium binders, vasodilator therapy, renal sympathetic denervation andagents targeting the gut microbiota. (J Am Coll Cardiol 2013;62:485–95) ª 2013 by the American College ofCardiology Foundation

The pathophysiology of advanced congestive heart failure(CHF) is complex and insufficiently elucidated. Historically,poor forward flow (i.e., low cardiac output), resulting inunrestrained neurohumoral up-regulation, has been con-sidered the main culprit mechanism (1). However, growingevidence has emphasized the concurrent importance ofbackward failure (i.e., systemic congestion) in both in thepathophysiology and disease progression of CHF (2).Coexisting renal dysfunction often complicates the treat-ment of CHF and occurs more frequently in patients withincreased cardiac filling pressures (3–8). Nevertheless,current pathophysiological models unsatisfactorily explain

ment of Cardiology, Ziekenhuis Oost-Limburg, Genk, Belgium;

for Medicine and Life Sciences, Hasselt University, Diepenbeek,

ical Research Institute, Faculty of Medicine and Life Sciences,

Diepenbeek, Belgium; xIntensive Care and High Care Burn Unit,

rk Antwerpen, Campus St. Erasmus, Antwerp, Belgium; and the

ardiovascular Medicine, Heart and Vascular Institute, Cleveland

Ohio. Drs. Verbrugge, Grieten, and Mullens are researchers for the

esearch Program (LCRP) UHasselt-ZOL-Jessa, supported by the

urg Sterk Merk (LSM), Hasselt University, Ziekenhuis Oost-

Hospital. All other authors have reported that they have no rela-

to the contents of this paper to disclose.

ived January 20, 2013; revised manuscript received April 8, 2013,

2013.

the detrimental link between congestion and cardiorenalfunction.

The abdominal compartment might contribute signifi-cantly to deranged cardiac as well as renal function in CHF.Abdominal symptoms of congestion are not uncommon inCHF, with constrictive pericarditis and restrictive cardio-myopathies being extreme examples in which splanchnicvenous hypertension and the formation of ascites oftenoccur. However, more subtle changes are generally over-looked and seldom recognized as potential drivers of diseaseprogression. This review explores potential maladaptivederangements in the abdominal compartment that mightaffect cardiorenal efficiency in CHF. Further, emergingtreatment strategies and potential new therapeutic targets,with a focus on the abdominal compartment, are discussed.A summary of the available evidence regarding this topic isprovided in Table 1.

Components and Function of theAbdominal Compartment

The splanchnic vasculature: capacitance function andcardiac pre-load. Three splanchnic arteries (the celiac trunkand superior and inferior mesenteric arteries) supply all

Abbreviationsand Acronyms

ADHF = acute

decompensated heart failure

ANP = atrial natriuretic

peptide

cAMP = cyclic adenosine

monophosphate

CHF = congestive heart

failure

IAP = intra-abdominal

pressure

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abdominal organs with blood.Individual organ perfusion largelydepends on pre-capillary arteri-olar vascular tone. In contrast,post-capillary venules and veinsall converge in the hepatic portalvein, which returns the blood tothe effective circulatory volumeafter passage through the liver. Innormal circumstances, splanchniccapacitance veins contain 25% ofthe total blood volume (9). Asthey pool and release blood in the

face of a changing volume status, those veins play a crucialrole in maintaining an optimal cardiac pre-load (10). Indeed,as much as 65% of blood volume added to an euvolemiccirculatory system is buffered in the splanchnic vasculaturewithout systemic hemodynamic effects (11). Under physio-logical circumstances, the transmural splanchnic venouspressure mimics changes in arterial blood flow (12). Thismeans that if arterial flow decreases, elastic recoil of theveins mitigates the resulting decrease in pressure, and adriving force for expulsion into the systemic circulationis maintained (Fig. 1). Importantly, although splanchnicarterioles contain both a- and b2-receptors that mediatevasoconstriction and vasodilation, respectively, the latter arenot abundant in capacitance veins (13). Therefore, sympa-thetic stimulation through epinephrine and/or norepineph-rine invariably causes venoconstriction, thereby reducingsplanchnic capacitance and recruiting effective circulatoryvolume (10).

In CHF, because of backward failure and increased arte-riolar vasoconstriction, a progressive shift of blood from theeffective circulatory volume to splanchnic capacitance veinsmight be expected. Although this remains speculative, onecould argue that splanchnic capacitance function ultimatelybecomes maladaptive in advanced CHF as a result of long-standing venous congestion and/or increased neurohumoralactivation (14). Indeed, cardiac filling pressures generallystart to increase w5 days preceding an admission for acutedecompensated heart failure (ADHF) (15,16). Although thiscan reflect a state of effective venous congestion as a result ofthe gradual build-up of volume, an equal proportion ofpatients gain <1 kg of weight during the week beforeadmission (17). This suggests that transient venoconstriction,presumably because of increased sympathetic stimulationwith redistribution of blood from (splanchnic) venouscapacitance beds to the effective circulatory volume, is analternative cause of increased cardiac filling pressures.Obviously, the relationship between intravascular pressureand volume is highly dynamic instead of simply linear, butthe need for increased splanchnic congestion is a prerequisitebefore cardiac filling pressures start to increase.The splanchnicmicrocirculation: lymphflowand interstitialedema. With few exceptions, Starling forces inthe microcirculation favor continuous net filtration (18).

Therefore, especially in the case of congestion with increasedcapillary hydrostatic pressure and resulting hyperfiltration,adequate lymph flow is key to preserve fluid homeostasis(Fig. 2, left). Physiologically, the interstitium exhibits lowcompliance, thereby driving excess fluid straight into thelymphatic system (19). Moreover, hydration of mucopoly-saccharides in the interstitial matrix increases the hydraulicconductivity of the interstitium and expands the distributionvolume of interstitial proteins, keeping their concentration low(20). As a result, hyperfiltration is met with increased lymphefflux. Importantly, because of solvent drag, lymph flowwashes out interstitial proteins, which decreases interstitialcolloid osmotic pressure and opposes increased filtration forces(18,21). Thus, a bidirectional interaction between net filtra-tion rate and Starling forces is present.

However, once lymph efflux reaches a maximum rate, thisdelicate balance will change (Fig. 2, right). If the interstitialfluid with filtrated solutes is inadequately drained, protein-rich edema will form, expanding the interstitial compart-ment significantly (22). The interstitium now enters a highcompliance state, which facilitates further edema accumu-lation (19).

Cardio-Abdominal-Renal Interactions inCongestive Heart Failure

Increased intra-abdominal pressure as amarkerof abdominalcongestion. In advanced CHF, inefficient natriuresis withprogressive volume overload may ultimately lead to a state ofsystemic congestion with increased intra-abdominal pressure(IAP) if capacitance function of the splanchnic vasculature isinsufficient and the splanchnic microcirculation unable tocope with congestion. IAP can easily be measured througha bladder catheter connected to a pressure transducer (23).Depending on body mass index and body position, normalIAP measurements in healthy adults are between 5 and 7mm Hg (24). However, in 60% of patients admitted withadvanced CHF, IAP exceeds this value (23). Remarkably,frank ascites is found in only a small subset of these patients,suggesting the presence of splanchnic venous and/or inter-stitial congestion as the reason for increased IAP. In criti-cally ill patients, intra-abdominal hypertension (IAP �12mm Hg) is a common cause of organ dysfunction (25). Inadvanced CHF, already small increases in IAP, in the rangeof 8 to 12 mm Hg, are associated with impaired renalfunction (23). Importantly, reversing increased IAPby decongestive therapy ameliorates serum creatinine inthis setting, presumably by alleviating abdominal congestion(23,26).The liver in CHF. Hepatorenal syndrome is a well-knowncomplication of chronic liver disease caused by overzealousvasodilation of the splanchnic circulation, resulting in arterialunderfilling and intense renal vasoconstriction (27). Liverdysfunction is frequent in CHF, related to backward failureand characterized by a predominantly cholestatic enzymeprofile associated with disease severity and prognosis (28,29).

Table 1 Review of the Literature on Abdominal Alterations Underlying Cardiorenal Dysfunction in Congestive Heart Failure

First Author, Year (Ref. #) Study Design Main Findings

Studies linking (abdominal)congestion to worseningrenal function

Mullens et al., 2008 (23) Prospective observational studyof 40 patients with advanced heart failure

Elevated intra-abdominal pressure is frequentin advanced heart failure and related to renal dysfunction

Mullens et al., 2008 (26) Prospective observational studyof 9 patients with advanced heart failure

Paracentesis- or ultrafiltration-related decreasesof intra-abdominal pressure are correlated with improvedrenal function

Nohria et al., 2008 (3) Prospective randomized studyof 433 patients with hemodynamic-guidedtherapy vs. clinical assessment alone

Correlation between right atrial pressure and serum creatinine

Damman et al., 2009 (4) Retrospective data review of 2,557 patientswith right heart catheterization

Central venous pressure >6 mm Hg associatedwith steep decrease in renal function

Mullens et al., 2009 (5) Prospective observational study of 145 patientswith advanced heart failure

Worsening renal function showed a strong correlationwith central venous pressure, and was independent ofcardiac index

Testani et al., 2010 (6) Retrospective review of 141 heart failure patientswith congestion assessed by echocardiography

Right ventricular failure leads to venous congestion and therelief of congestion likely drives improvement in renal function

Verhaert et al., 2010 (7) Prospective observational study of 62 patientswith advanced heart failure

Patients with right ventricular dysfunction that improves afterdecongestive treatment have a better outcome

Guglin et al., 2011 (8) Retrospective data review of 178 patientswith right heart catheterization

Renal dysfunction relates to high cardiac filling pressuresand lower renal perfusion pressure

Studies suggesting volumeredistribution as a causefor elevated cardiac fillingpressure

Adamson et al., 2003 (15) Prospective, observational study of32 heart failure patients with animplantable hemodynamic monitor

Right-sided cardiac filling pressures start to increase w5 dayspreceding an admission for acute decompensated heart failure

Chaudhry et al., 2007 (17) Nested case-control study of 134heart failure patients followed by telemonitoring

Only 46% of patients presenting with acutedecompensated heart failure gain >2 lb in weight

Zile et al., 2008 (16) Substudy of COMPASS-HF study (N ¼ 274) The transition from chronic to acute decompensatedheart failure is associated with a progressive increasein cardiac filling pressures

Studies on cardiohepaticinteractions in heart failure

Ahloulay et al., 1996 (33) Animal study (rats) Hepatorenal pathway through extracellular cyclicadenosine monophosphate influences natriuresis in thepresence of ascites

Ming et al., 2002 (30) Animal study (rats) Decreased portal blood flow triggers sodium and water retention

Poelzl et al., 2012 (28) Prospective observationalstudy of 1,032 heart failure patients

Liver dysfunction is frequent in patients withcongestive heart failure and prognostically important

Poelzl et al., 2013 (29) Prospective observational study of 1,290heart failure patients, includinginvasive hemodynamics in 253 patients

Renal and liver dysfunction are independent negativepredictors of worse outcome in heart failure and related tocongestion rather than impaired cardiac output

Studies on cardiosplenicinteractions in heart failure

Sultanian et al., 2001 (39) Animal study (rats) Atrial natriuretic factor increases splenic microvascularpressure and fluid extravasation

Hamza et al., 2004 (42) Animal study (rats) Decreased splenic blood flow triggers sodium and water retention

Studies on gut-derivedhormones in heart failure

Carrithers et al., 2000 (45) Case-control study with 16 heart failurepatients and 53 healthy individuals

Heart failure patients have an increased uroguanylin excretion,which has natriuretic properties and is produced by the gut

Narayan et al., 2010 (46) Case-control study with 243 heart failurepatients and 53 healthy individuals

Prouroguanylin and proguanylin levels are increased in patientswith heart failure, especially in severe heart failure withconcomitant renal dysfunction

Studies on impaired intestinalbarrier function in heart failure

Sandek et al., 2007 (50) Prospective observation study of22 patients with heart failure

Intestinal morphology, permeability, and absorptionare altered in heart failure

Arutyunov et al., 2008 (51) Case-control study with 45 heartfailure patients and 18 healthy individuals

Patients with heart failure demonstrate collagen accumulationand dysfunctional mucosal barrier of the small intestine

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Figure 1 The Splanchnic Vasculature: Capacitance Function and Cardiac Pre-load

Splanchnic capacitanceveins ensurea stable cardiac pre-load in the face of a changing volumestatus. First, if arteriolar perfusiondrops, elastic recoil of the veinsmaintainsa driving

force for venous return. Second, sympathetic stimulation because of centrally perceived hypovolemia leads to a-mediated vasoconstriction of splanchnic capacitance veins, but b2-mediated vasodilation of the hepatic veins. Consequently, autotransfusion from the splanchnic capacitance veins occur to increase the effective circulatory volume.

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As advanced liver dysfunction negatively affects cardiorenalfunction, a vicious cycle might be created. In addition, it isnotable that the portal vein contains a-adrenergic receptorsbut not b2-receptors, whereas the latter are abundant inhepatic veins (13). As a result, sympathetic stimulationmight be expected to decrease post-hepatic vascular resis-tance and shift blood to augment cardiac pre-load, whichcould be harmful in ADHF (Fig. 1). Moreover, data fromanimal studies show that decreased intrahepatic blood flow,as caused by a-adrenergic–mediated portal vasoconstriction,leads to accumulation of intrahepatic adenosine, which isproduced by the metabolism of hepatocytes and leaves theliver through the lymphatic and venous systems (Fig. 3).Increasing local adenosine stimulates hepatic afferent nerveactivity in rats, triggering a hepatorenal reflex as hepaticafferent nerves synapse on renal efferent nerves (30). Thisresults in renal vasoconstriction, whereas sodium retention ispromoted. Finally, some intriguing animal data from a ratmodel of ascites link cyclic adenosine monophosphate(cAMP) production by the liver to renal sodium homeostasis(31). cAMP, widely known as a second messenger, also actsas a distant messenger produced by the liver and regulatingsodium reabsorption in the proximal renal tubules. Indeed,

extracellular cAMP produced by hepatocytes in response toglucagon increases natriuresis and phosphate excretion ina dose-dependent manner in humans (32). Remarkably, thisresponse is blunted in rats that have cirrhosis with ascites,possibly because of liver dysfunction (33). Therefore, livercongestion in CHF might directly contribute to a state ofimpaired natriuresis.The spleen in CHF. The spleen, which constitutes anintegral part of the splanchnic vasculature, receives w5% ofthe cardiac output, making it a perfectly placed organ toregulate intravascular volume (34,35). The splenic vein joinsthe superior mesenteric vein to form the hepatic portal vein,allowing splenic hemodynamics to modulate splanchniccongestion. It has been shown that after volume expansion,fluid is accumulating in the gel-like lymphatic matrix withinconnective tissues surrounding the splenic vascular arcade(36). Importantly, fluid from this splenic lymphatic reservoirhas the same protein content as splenic venous blood, whichsuggests that splenic capillaries are freely permeable toplasma proteins (36). Thus, intrasplenic extravasation ofiso-oncotic fluid is directly dependent on intraluminalhydrostatic pressure and consequently related to congestionin the splanchnic vasculature (Fig. 4). Interestingly, atrial

Figure 2 The Splanchnic Microcirculation: Lymph Flow and Interstitial Edema

Net filtration rate in the splanchnic microcirculation is determined by Starling forces: (PC � PIF) � (pC � pIF). PC ¼ capillary hydrostatic pressure; PIF ¼ interstitial fluid hydrostatic

pressure; pC ¼ capillary oncotic pressure; pIF ¼ interstitial fluid oncotic pressure. (Left, compensated state): PC (35 to 45 mm Hg arteriolar to 12 to 15 mm Hg venular), PIF (�2

mm Hg) and pIF (16 mm Hg) all favor filtration (green arrows), whereas pC (25 to 28 mm Hg) opposes filtration (red arrows). Therefore, net filtration prevails over the entire

length of the splanchnic capillary with net filtration pressure decreasing from 32 mm Hg (arteriolar side) to 4 mm Hg (venular side). In case of congestion with increased PC, net

filtration pressure is even higher. Therefore, abdominal lymph flow (QL) is important to drain fluid and solutes. Normally, the interstitium exhibits low compliance. Thus, excess

filtrated fluid is drained straight into lymphatic capillaries, allowing only a limited build-up of interstitial fluid volume (VIF). Consequently, QL can increase as much as 20 times its

normal value (22). Importantly, increased QL washes out interstitial proteins, which decreases pIF, opposing filtration. In this state of compensated splanchnic congestion,

increased net filtration because of increased PC is met by enhanced QL, thereby preventing the accumulation of interstitial fluid. (Right, interstitial edema): Once a critical flow is

reached, QL cannot increase further. In addition, from a PIF of w2 mm Hg, the interstitium enters a high compliance state (19). Both lead to VIF expansion. As lymph flow is now

deficient in washing out interstitial proteins, protein-rich edema arises and compresses lymphatics, impeding lymph flow and promoting edema formation even further.

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natriuretic peptide (ANP) infusions in rats cause hemo-concentration and a reduction in plasma volume that is notentirely explained by urinary losses alone (37). This obser-vation, however, is virtually abolished in animals previouslysplenectomized (38). The reason for this phenomenon isthat ANP alters splenic hemodynamics (i.e., increasesintrasplenic pressure) by specific and direct actions on thesplenic microvasculature (39). Although evidence is onlypreliminary, this might have important pathophysiologicalimplications in CHF (Fig. 4). One could speculate that,initially, increased fluid efflux through the spleen into thelymphatic vasculature might help to reduce splanchniccongestion. However, in a more advanced state, especiallywhen high ANP is present, a paradoxical reduction ineffective arterial blood volume might develop, as continuous

fluid efflux out of the intravascular space might exacerbateperceived central hypovolemia. At the same time, as splanchniccongestion worsens, intrasplenic microvascular pressure re-mains increased and fluid efflux out of the spleen continuesin a vicious cycle, overloading the lymphatic system andleading to an accumulation of excess fluid in the perivascularthird spaces. Indeed, CHF is the fourth most common causeof splenomegaly after hepatic disease, hematological disor-ders, and infection (40,41). Moreover, in this context, asplenorenal reflex, similar to the hepatorenal reflex, has beendemonstrated (42).Gut-derived hormones in CHF. Further supporting a roleof the abdominal compartment in renal sodium handling andvolumehomeostasis are the peptides uroguanylin and guanylin.Both are involved in the regulation of water and electrolyte

Figure 3 The Liver in Congestive Heart Failure: Hepatorenal Reflex

Hepatocytes continuously produce adenosine as a byproduct from the breakdown of adenosine triphosphate. Adenosine accumulates in the perisinusoidal space, which is

drained by the lymphatic system. When portal blood flow is reduced because of a-receptor–mediated vasoconstriction, lymph flow will decrease and intrahepatic concentrations

of adenosine increase. As a result, hepatic afferent nerves are stimulated, which subsequently synapse on renal efferent nerves. Consequently, renal vasoconstriction and

sodium retention are promoted.

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transport in the gut and share natriuretic properties mediatedby a cyclic guanosine monophosphate–dependent mechanism(43). Their role in regulating the sodium balance via anintestinal-renal pathway has been demonstrated, as it isobserved that an oral sodium intake evokes more rapid natri-uresis than an equivalent intravenous load (44). Urinaryexcretion of uroguanylin is increased in patients with CHF,whereas increased plasma levels of the precursor proteins pro-guanylin and prouroguanylin are correlated with the severity ofCHF symptoms assessed by New York Heart Associationfunctional class (45,46).Thus, analogous to the congestedheartproducing ANP and B-type natriuretic peptide, there seems tobe an intestinal natriuretic peptide that is increased in patientswith CHF who presumably have abdominal congestion. Yet,the exact pathophysiological role of uroguanylin and guanylinin CHF remains to be determined.The gut in CHF: the intestinal barrier function, gutmicrobiota, and uremic toxicity. Arterioles, capillaries, andvenules have a peculiar organization in the intestinal

microcirculation, forming a countercurrent system thatstrongly resembles the vasa recta of the renal medulla(Fig. 5A) (47). As a result, the intestinal villus can buildup an interstitial concentration gradient with the highestosmolality at its tip, which is needed for continuous fluidabsorption. However, a drawback of this system is thatarteriolar oxygen short circuits to venules before reaching thevillus tip, making this place particularly susceptible to anoxicdamage (47). Because of low perfusion (i.e., low cardiacoutput), congestion (i.e., increased central venous pressure),and increased sympathetic vasoconstriction, CHF patientsare at risk of nonocclusive bowel ischemia (Fig. 5B) (48).Importantly, the combination of hypoxia and local produc-tion of lipopolysaccharides by gram-negative bacteria residingin the gut lumen causes an increase in the paracellularpermeability of the intestinal wall (49). Indeed, it has beenshown that the intestinal morphology, permeability, andfunction are substantially altered in CHF, especially inadvanced states with cardiac cachexia (50,51). Moreover,

Figure 4 The Spleen in Congestive Heart Failure: A Regulator of Intravascular Volume

Splenic sinusoids are freely permeable to plasma proteins. As a result, the colloid osmotic pressure inside the splenic sinusoids is the same as in the surrounding lymphatic

matrix, and fluid transport between the 2 spaces is determined by differences in hydrostatic pressure. Transient congestion of the splanchnic venous system results in an

increased hydrostatic pressure inside the splenic sinusoids. Therefore, more fluid is drained to the lymphatic matrix and buffered inside the lymphatic reservoirs of the spleen.

However, especially in the presence of increased cardiac filling pressures and resulting atrial natriuretic peptide (ANP) production, splenic arterial vasodilation, and venous

vasoconstriction greatly enhance the fluid shift to the perivascular third space inside the spleen. This might lead to perceived central hypovolemia, exacerbating neurohumoral

stimulation and creating a vicious cycle. Moreover, the lymphatic system becomes overloaded, which results in interstitial edema. PLM ¼ lymphatic matrix hydrostatic pressure;

PSS ¼ splenic sinusoidal hydrostatic pressure; pLM ¼ lymphatic matrix colloid osmotic pressure; pSS ¼ splenic sinusoidal colloid osmotic pressure.

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concomitant uremia caused by renal dysfunction alters thebacterial colonization of the gut and may also contributeto increased intestinal permeability (52,53). It has beendemonstrated that microbiota are the cause of fermentationprocesses in the gut, which produce protein-bound uremictoxins that are ineffectively cleared from the circulation incases of renal dysfunction (54,55). Moreover, lipopolysac-charide in the circulation triggers systemic inflammationand cytokine generation (i.e., tumor necrosis factor-a,interleukin-6), which results in depression of excitation-contraction coupling, decreased peak velocity of cardio-myocyte shortening, disturbed mitochondrial respiration, andimpaired substrate metabolism in cardiomyocytes (56–58).

New Diagnostic Opportunities

From a clinical point of view, it is obvious that despiteaggressive diuretic therapy and treatment with neurohumoralblockers, a subset of patients present with persistent signs andsymptoms of congestion. Although the presence of frankascites clearly represents the most extreme side of a spectrum,abdominal congestion remains difficult to evaluate at thebedside. As explained, IAP is potentially a useful surrogatemarker for abdominal congestion and can easily be measuredvia a bladder catheter connected to a pressure transducer (23).Noninvasive alternatives for patients without a bladdercatheter have emerged in the field of laparoscopic surgery, but

Figure 5 The Gut in Congestive Heart Failure: The Intestinal Barrier Function

(A) The countercurrent system of the intestinal microcirculation makes extensive exchange possible between arterioles and venules. As a result, oxygen (O2) short circuits from

arterioles to venules, creating a gradient with the lowest partial O2 pressure at the villus tip. (B) In congestive heart failure, there is a low-flow state in the splanchnic

microcirculation because of low perfusion, increased venous stasis, and sympathetically mediated arteriolar vasoconstriction, which stimulates O2 exchange between arterioles

and venules, exaggerating the gradient between the villus base and tip. This causes nonocclusive ischemia, resulting in dysfunctional epithelial cells and loss of intestinal

barrier function. As a result, lipopolysaccharide or endotoxin, produced by gram-negative bacteria residing in the gut lumen, enter the circulatory system.

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are currently not sensitive enough to evaluate small changes inthe range described in CHF patients (59). Therefore, aninteresting alternative would be to visualize the microcircu-lation directly. As such, new evolving techniques such asorthogonal polarized spectral and side-stream dark field allowassessment of alterations in the microcirculation of the patientat the bedside (60). Moreover, a better evaluation of renal,hepatic, and splenic hemodynamics might improve the

phenotyping of patients presenting with acute decom-pensated heart failure. Noninvasive echocardiographymeasurements or even measuring the portal “wedge” pressureduring right-sided heart catheterization might offer amplenew diagnostic opportunities (61–63). Obviously, betterinsight into cardio-abdominal-renal interactions with regardto different heart failure phenotypes (i.e., heart failure withreduced versus preserved ejection fraction, left- versus right-

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sided heart failure) is needed and an area of future research.Importantly, because congestion is a characteristic feature ineach of these conditions, abdominal contributions to patho-physiology might be a major focus of interest.

New Treatment Strategies and Therapeutic Targets

Relieving abdominal congestion. In advanced CHF withincreased IAP and ascites, paracentesis might be useful tocorrect fluid loss in the perivascular third spaces and toimprove renal function (26). In addition, it has been shownthat mechanical fluid removal through ultrafiltration removesmore sodium in the same amount of water compared withdiuretics (64). Therefore, ultrafiltration has the potential toreduce interstitial edema more efficiently in CHF. However,as was recently demonstrated in the CARRESS-HF (Car-diorenal Rescue Study in Acute Decompensated HeartFailure) study, the need for central venous access is associatedwith potential complications, and a strategy with diuretics iftitrated to urinary output and including combination therapy,is generally successful in achieving decongestion (65).Therefore, we would recommend ultrafiltration only in thecase of clear systemic congestion refractory to combinationtherapy with diuretics and with the ultrafiltration rate guidedby central hemodynamics to avoid intravascular volumedepletion. However, prognosis is often sobering in such caseswith high mortality, and often a need for continued renalreplacement therapy (66).

Continuous ambulatory peritoneal dialysis offers a(physiological) therapeutic alternative in patients with CHFand concomitant renal dysfunction. Recently, 2 studies re-ported improvements in symptoms, physical performance,quality of life, and biochemical profile after initiation ofperitoneal dialysis in a pooled cohort of 143 patients withadvanced CHF, impaired renal function, and persistentcongestion despite therapy with high-dose loop diuretics(67,68). As peritoneal dialysis provides continuous slowultrafiltration, it has a minimal impact on hemodynamicsand consequently neurohumoral stimulation (69). In addi-tion, sodium and potassium are effectively removed, po-tentially allowing better up-titration of neurohumoralblockers (69). Finally, although speculative, providing apermanent outlet of the abdominal cavity might reduce IAP,which has been demonstrated to improve renal function inCHF (26,69). Nevertheless, current evidence from obser-vational, small, single-center studies should be consideredhypothesis-generating, requiring confirmation by a random-ized clinical trial.

Targeting maladaptive responses in the abdominalcompartment. SODIUM AVIDITY AND ORAL SODIUM BIND-

ERS. As already explained by the neurohumoral model,impaired natriuresis is a typical finding in CHF (1).Remarkably, early in the disease process, before emergingsymptoms or impaired central hemodynamics, sodiumavidity is present, which initially can be overcome with theadministration of exogenous natriuretic peptides (70).

However, in more advanced CHF, high concentrations ofnatriuretic peptides might be insufficient to prevent systemiccongestion and could even contribute to perceived centralhypovolemia and fluid accumulation in perivascular thirdspaces. Indeed, this explains the overall neutral results andhigh incidence of hypotension with nesiritide (a syntheticanalog of human B-type natriuretic peptide) in theASCEND-HF (Acute Study of Clinical Effectiveness ofNesiritide in Decompensated Heart Failure) study ina population with advanced CHF admitted with ADHF(71). Hypothetically, using natriuretic peptides earlier in thedisease process to counter sodium avidity might be morephysiologically reasonable.

Despite typical recommendations of salt restriction,diuretics are usually needed to achieve a neutral sodiumbalance in CHF. Although bias by indication almost certainlyplays a role, the correlation between a higher dose of loopdiuretics and adverse outcome in CHF remains a concern(72). Oral sodium binders target sodium absorption in the gutand are an emerging therapeutic strategy in CHF (73).Because they prevent sodium and fluid accumulation withoutinfluencing hemodynamics, they have the benefit of notcausing further maladaptive neurohumoral stimulation.

VASODILATOR THERAPY. Vasodilator therapy in addition toneurohumoral blockers to recruit venous capacitance veins isan appealing strategy to treat misdistribution of bloodvolume. Venous vasodilation might temporarily improve thebuffer capacity of the splanchnic vasculature, whereas arte-riolar vasodilation increases the effective circulatory volumeon which the kidneys exert their regulating function.Moreover, left ventricular wall tension and afterload will bereduced as well, which improves hemodynamics and organperfusion, especially when cardiac output is impaired(74,75). Interestingly, targeting cardiac filling pressuresprimarily by adding vasodilator therapy reduced admissionsfor ADHF by >30% in the CHAMPION (CardioMEMSHeart Sensor Allows Monitoring of Pressure to ImproveOutcomes in NYHA Class III Heart Failure Patients) trial,with similar benefits in both patients with reduced andpreserved ejection fraction (76). Indeed, a lower dose ofdiuretics is needed for the same amount of decongestionwhen vasodilators are added (77). Specific data regarding therole of vasodilators to improve renal function in patientswith cardiorenal syndrome are lacking, but low-dose dopa-mine and nesiritide, both sharing renal vasodilator proper-ties, are currently under investigation in the ROSE AHF(Renal Optimization Strategies Evaluation in Acute HeartFailure) trial (NCT01132846).

RENAL SYMPATHETIC DENERVATION. Unrestrained sympa-thetic up-regulation is one of the many factors drivingsodium avidity in CHF (1). Moreover, because of theabundance of a-receptors in the splanchnic vasculature, itmight cause venoconstriction, thereby increasing the effec-tive circulatory volume (13). Furthermore, animal experi-ments have demonstrated the existence of both a hepatorenal

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and splenorenal reflex, mediated by renal efferent nerves andcausing renal vasoconstriction with consequently low renalblood flow that might impair renal function (30,42). Finally,sympathetic stimulation presumably contributes to non-occlusive bowel ischemia through arteriolar vasoconstrictionin CHF. Because all these effects are mediated by a-receptors and thus not targeted by b-blocker therapy, renalsympathetic denervation might be an appealing strategy tolower sympathetic drive in general and target both afferentand efferent sympathetic nerves (78).Altering gut microbiota and preserving the intestinalbarrier function. Although interesting from a pathophysio-logical point of view, there really is a lack of knowledge abouthow to exploit the symbiosis of the human body with gutmicrobiota. Current CHF therapies like b-blockers andangiotensin-converting enzyme inhibitors probably havebeneficial effects, whereas the value of probiotics, selectivebowel decontamination, endotoxin immunoadsorption, N-acetylcysteine, and other immunomodulators have yet to beelucidated (48). Rifaximin, a virtually unabsorbable antibioticwith broad-spectrum activity against both gram-negative and-positive, has recently shown some promising results in thisrespect. In patients with decompensated liver cirrhosisand ascites, it improved systemic hemodynamics and renalfunction, presumably by inhibiting gut inflammation,resulting in toxin entrance into the circulatory system (79).

Conclusions

Although patients frequently present with abdominal symp-toms, especially when they have marked signs and symptomsof congestion, the abdomen remains largely understudied inCHF. Although not always easy to evaluate at the bedside,cardio-abdominal-renal interactions most probably play animportant role in the development of persistent systemiccongestion despite adequately dosed diuretic therapy.Better insight into these interactions by understanding thecapacitance function of splanchnic blood vessels, thesplanchnic organs, and the microcirculation might offera venue for new diagnostic and therapeutic strategies in CHF.

Reprint requests and correspondence: Dr. Wilfried Mullens,Department of Cardiology, Ziekenhuis Oost-Limburg, SchiepseBos 6, 3600 Genk, Belgium. E-mail: wilfried.mullens@zol.be.

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Key Words: congestive heart failure - gut - microcirculation -

splanchnic circulation.